Diltiazem hydrochloride, a benzothiazepine derivative, is a calcium channel blocker used in the treatment of angina and hypertension. The solubility of diltiazem significantly decreases as the pH increases in the gastrointestinal tract. It is required, however, that a drug delivery system deliver the drug at a constant rate as it is transported from the region of low pH in the stomach to a region of higher pH in the intestine. Such controlled delivery results in a decrease in the frequency of drug administration thereby improving patient compliance. Furthermore, controlled drug delivery systems produce constant plasma levels of active ingredients as compared to fluctuations seen when multiple doses of a conventional formulation are prescribed. Thus, controlled drug delivery systems may decrease the severity and frequency of side effects.
Several controlled drug delivery systems which are adapted for the delivery of the drug diltiazem and other drugs are known in the prior art.
U.S. Pat. No. 4,894,240 describes a controlled release diltiazem pellet formulation for once-daily oral administration consisting of a core comprising diltiazem and an organic acid, followed by a multilayer membrane surrounding the core. The membrane comprises a combination of water insoluble polymers and a minor amount of water soluble polymers. The number of layers in the membrane and the ratio of water soluble to water insoluble polymers are formulated so that diltiazem is released in a controlled manner. A formulation as described by this patent is sold in the United States under the trademark Cardizem CD.TM. by Hoechst-Marion-Roussel. Other patents that are related to the Cardizem CD.TM. pellet formulation include U.S. Pat. Nos. 5,002,776; 5,286,497; and 5,470,584. Similar pellet formulations for twice-daily oral administration are disclosed in U.S. Pat. No. 4,721,619 and are sold by Hoechst-Marion-Roussel in the United States under the trademark Cardizem SR.TM. by Hoechst Marion Roussel.
U.S. Pat. No. 4,917,899 discloses a controlled release diltiazem pellet formulation wherein a core of diltiazem is coated with multiple layers of water insoluble polymers. Slow release and fast release pellets are then filled into hard gelatin capsules such that the fast release pellets amount to 15% of the total blend. The formulation releases diltiazem over a 12 hour period such that it is suitable for a twice-a-day oral dosing regimen.
U.S. Pat. No. 4,839,177 discloses a controlled drug delivery system comprising a core having a defined geometry and containing a swellable and/or gellable polymeric material, and a suitable platform containing a water insoluble polymeric material applied to the core in the form of a partial coating. The intensity and duration of the swelling force and the geometry of the device are identified as factors determining the release of the active substance. Such a system is sold in the United States under the trademark Dilacor XR.TM. by Rhone-Poulenc Rorer. Another patent related to the Dilacor XR.TM. formulation is U.S. Pat. No. 5,422,123 with the difference being that the support platform described in the latter patent is an elastic support which is slowly soluble or gellable in aqueous fluids.
U.S. Pat. No. 5,529,791 discloses an extended release galenical composition comprising beads containing one or more diltiazem salts and an effective amount of a wetting agent in admixture with one or more diltiazem salts to maintain the solubility of diltiazem in each bead. The beads are coated with a microporous membrane comprising at least a water soluble or water dispersible polymer or copolymer, a water-, acid- and base-insoluble polymer, and a pharmaceutically acceptable adjuvant. A formulation as described in this patent is sold in the United States under the trademark Tiazac.TM. by Biovail.
U.S. Pat. No. 4,968,507 discloses an osmotic pump comprising a core containing at least one active agent and an osmotic agent surrounded by a water insoluble wall with a defined permeability to water but which is impermeable to solute, and containing at least one pH insensitive pore forming additive dispersed throughout said wall.
U.S. Pat. No. 4,880,631 discloses an osmotic pump similar to that disclosed in U.S. Pat. No. 4,968,507 (discussed below) but specifically containing diltiazem-L-malate as the active ingredient. A formulation as described by this patent is sold in the United States under the trademark Tiamate.TM. by Merck & Co.
European Patent App. No. 373,417 discloses a sustained release diltiazem once-daily tablet formulation with the drug dispersed in a hydrophobic matrix comprising one or more of ethylcellulose, a mixture of mono- and diglycerides, cellulose acetate, calcium phosphate, cellulose acetate butyrate and microcrystalline cellulose. Further, the document describes a water soluble coating comprising a swelling hydrophilic polymer or a barrier coating comprising a water-insoluble polymer, an enteric polymer or a mixture thereof.
European Patent App. No. 381,181 discloses a core containing diltiazem or other active agent and an osmotically active substance coated by a semi-permeable wall forming material.
U.S. Pat. No. 4,792,452 discloses a controlled release pharmaceutical formulation comprising a drug, a pH-dependent polymer which is an alginic acid salt, a pH-independent hydrocolloid gelling agent and a binder. The formulation is Ca.sup.+2 ion free. The drug is released independent of the pH of the environment.
U.S. Pat. No. 4,946,686 describes a solubility modulated drug delivery system in which the core is comprised of a water soluble drug and a controlled release solubility modulator which is either a complexing agent or a surfactant. The core is surrounded by a water insoluble microporous wall containing pore forming additives.
U.S. Pat. No. 4,994,273 describes a solubility modulated drug delivery system in which the core is made of a water soluble drug and a solubility modulating agent comprising a complexing agent or a surfactant. The core is surrounded by a water insoluble semi-permeable wall.
U.S. Pat. No. 4,968,508 discloses a matrix tablet formulation for cefaclor, comprising from about 5% by weight to about 29% by weight of hydrophilic polymer, and from about 0.5% by weight to about 25% by weight of an acrylic polymer which dissolves at a pH in the range of between about 5.0 to about 7.4. The total weight of the polymers is less than 30% by weight of the system. The cefaclor is released within a few hours and is suitable for the administration of cefaclor twice daily.
U.S. Pat. No. 5,000,962 discloses a long acting diltiazem tablet comprising more than 35% by weight of a swellable hydrophilic polymer, a binder, a lubricant and diluent. Both coated and uncoated tablets are disclosed.
U.S. Pat. No. 5,578,321 discloses a tablet containing diltiazem hydrochloride suitable for once-daily oral administration. The tablet comprises not less than 30% by weight diltiazem hydrochloride and from 30% to 70% by weight hydroxypropyl methylcellulose having a number average molecular weight of at least 50,000.
The present invention provides a controlled drug delivery composition for once-daily administration of diltiazem to a human subject, the composition comprising diltiazem, one or more hydrophilic polymers, and an enteric polymer, wherein the ratios and amounts of enteric polymer and hydrophilic polymers are such that diltiazem is released at a constant rate over a range of pH. Enteric or pH-dependent polymers are insoluble at the acidic pH of the stomach but dissolve and/or erode in the higher pH range of about 5 to 8 encountered in the intestine. Therefore, at the lower pH in the stomach, enteric polymers impede drug release. At the higher pH in the intestine, the enteric polymers dissolve and/or erode. Thus, in spite of the higher solubility of the drug in acidic fluids, it is released at more or less the same rate throughout the pH range likely to be encountered in the gastrointestinal tract.
In addition to the use of a combination of defined ratios of hydrophilic and enteric polymers, the use of a high quantity of polymers in the present invention contributes towards ensuring a constant rate of release of the drug and therefore a uniform and consistent absorption. Effective plasma levels are maintained for a period as long as 24 hrs and persist near the minimum effective level for up to 30 hrs. This further ensures uniform blood level profiles and eliminates the risk of overdose. Such an elimination of risk of overdose is of particular concern in once-daily formulations as they contain a quantity of active medicament which is several times the conventional dose of the medicament.
The release of a drug from a matrix system is dependent on the physiochemical nature of the drug, and the present invention provides a composition comprising hydrophilic and enteric polymers in ratios and amounts that results in controlled release of diltiazem at a rate that benefits therapy with diltiazem.
The present invention is easy to produce. Prior art processes are either more time consuming or expensive. For example, the process for making the coated pellets in capsules such as Cardizem CD.TM. that are described in U.S. Pat. No. 4,894,240, and the drug delivery system of Dilacor XR.TM. described in U.S. Pat. No. 4,839,177, are complex and expensive to make.